OBJECTIVE: Protein S (PS) is a component of the protein C anticoagulant system. PS deficiency is associated with myocardial infarction and venous thromboembolism, two highly prevalent causes of death in industrialized nations. As part of the Genetic Analysis of Idiopathic Thrombophilia (GAIT) project, we conducted a genome-wide linkage screen to localize genes influencing variation in free PS (fPS) plasma levels. METHODS AND RESULTS: fPS levels were measured in 397 individuals in 21 Spanish families. A total of 363 highly informative microsatellite markers were genotyped to provide a 10-cM genetic map, and variance component linkage methods were used. A region on chromosome 1q32, flanked by markers D1S425 and D1S213, showed strong evidence of linkage with fPS levels (LOD score, 4.07; nominal P=7.5x10(-6); genome-wide P=0.0024). This region contains two positional candidate genes, the complement component 4-binding protein alpha and beta chains, which encode the principal binding protein for PS. Suggestive evidence for linkage was also observed on chromosomes 11p and 19p. CONCLUSIONS: These results represent one of the first genomic screens for quantitative variation in a component of the hemostatic pathway and provide strong evidence for a locus on chromosome 1q influencing fPS levels.
OBJECTIVE: Protein S (PS) is a component of the protein C anticoagulant system. PS deficiency is associated with myocardial infarction and venous thromboembolism, two highly prevalent causes of death in industrialized nations. As part of the Genetic Analysis of Idiopathic Thrombophilia (GAIT) project, we conducted a genome-wide linkage screen to localize genes influencing variation in free PS (fPS) plasma levels. METHODS AND RESULTS: fPS levels were measured in 397 individuals in 21 Spanish families. A total of 363 highly informative microsatellite markers were genotyped to provide a 10-cM genetic map, and variance component linkage methods were used. A region on chromosome 1q32, flanked by markers D1S425 and D1S213, showed strong evidence of linkage with fPS levels (LOD score, 4.07; nominal P=7.5x10(-6); genome-wide P=0.0024). This region contains two positional candidate genes, the complement component 4-binding protein alpha and beta chains, which encode the principal binding protein for PS. Suggestive evidence for linkage was also observed on chromosomes 11p and 19p. CONCLUSIONS: These results represent one of the first genomic screens for quantitative variation in a component of the hemostatic pathway and provide strong evidence for a locus on chromosome 1q influencing fPS levels.
Authors: Alfonso Buil; David-Alexandre Trégouët; Juan Carlos Souto; Noémie Saut; Marine Germain; Maxime Rotival; Laurence Tiret; Françcois Cambien; Mark Lathrop; Tanja Zeller; Marie-Christine Alessi; Santiago Rodriguez de Cordoba; Thomas Münzel; Philipp Wild; Jordi Fontcuberta; France Gagnon; Joseph Emmerich; Laura Almasy; Stefan Blankenberg; José-Manuel Soria; Pierre-Emmanuel Morange Journal: Blood Date: 2010-03-08 Impact factor: 22.113
Authors: Jorge Esparza-Gordillo; José Manuel Soria; Alfonso Buil; Laura Almasy; John Blangero; Jordi Fontcuberta; Santiago Rodríguez de Córdoba Journal: Immunogenetics Date: 2004-04-30 Impact factor: 2.846
Authors: A P Reiner; C L Carty; N S Jenny; C Nievergelt; M Cushman; D J Stearns-Kurosawa; S Kurosawa; L H Kuller; L A Lange Journal: J Thromb Haemost Date: 2008-08-01 Impact factor: 5.824
Authors: Georgios Athanasiadis; Alfonso Buil; Juan Carlos Souto; Montserrat Borrell; Sonia López; Angel Martinez-Perez; Mark Lathrop; Jordi Fontcuberta; Laura Almasy; José Manuel Soria Journal: PLoS One Date: 2011-12-28 Impact factor: 3.240